Individual differences in the development of neurofibrillary changes were examined in eight cortical regions in the brains of 43 subjects with Down syndrome (DS; age range, 15-69 years) using sections stained with monoclonal antibodies (mAb) tau-1 and 3-39. Neurofibrillary pathology was found in 4 cases below 36 years of age and in all 20 cases above that age. In the 24 positive cases, numerical density of pretangles stained with tau-1 and 3-39, respectively, was 6.1/mm2 and 0/mm2; early tangles, 5.0/mm2 and 5.3/mm2; mature tangles, 4.0/mm2 and 5.0/mm2 (p < 0.01); and end-stage tangles, 0.04/mm2 and 2.5/mm2 (p < 0.001). Numerical density of pretangles stained with mAb tau-1 and tangles and plaques stained with mAb 3-39 correlates weakly with age (r = 0.43; p< 0.02), and together with the wide range of numerical densities suggested heterogeneity of the population examined. Cluster analysis based on two variables - i.e., numerical density of pretangles stained with mAb tau-1 and neurofibrillary tangles (NFTs) and plaques stained with mAB 3-39, distinguished three groups of subjects with severe, moderate and weak changes. The severely affected group of 5 subject (21%) had an average 54.6/mm2 of neurons and 13.9/mm/ plaques with neurofibrillary changes, whereas the moderately affected group (6 subjects; 25%) showed a significantly lower numerical density of neurons and plaques with neurofibrillary changes (25.7/mm2 and 8.1/mm2, respectively) as compared with the most affected group. Most of the subjects (13; 54%) belong to the third group with only 2.2/mm2 of neurons and 1.4/mm2 plaques with neurofibrillary pathology. Comparison of these three groups of Down syndrome subjects representing high, moderate, and low susceptibility to neurofibrillary changes with the general population suggests that the risk of Alzheimer disease is similar but the onset of pathological changes is earlier in DS.